Rejected

Transient receptor potential vanilloid 4 (TRPV4) is a Ca-permeable non-selective cation channel that is involved in the development of neuropathic pain. P2X7 receptor (P2X7) belongs to a class of ATP-gated nonselective cation channels that plays an important role in neuropathic pain. Nevertheless, little is known about the interaction between them for neuropathic pain. In this paper, we investigated role of TRPV4-P2X7 pathway in neuropathic pain. We evaluated the effect of TRPV4-P2X7 pathway on neuropathic pain in a chronic compression of the dorsal root ganglion (DRG) (hereafter termed CCD) model. We analyzed the effect of P2X7 on mechanical and thermal hyperalgesia mediated by TRPV4 in CCD. Furthermore, we assessed the effect of TRPV4 on the expression of P2X7 and the release of IL-1β and IL-6 in DRG after CCD. We found that intraperitoneal injection of TRPV4 agonist GSK-1016790A led to a significant increase of mechanical and thermal hyperalgesia in CCD, which was partially suppressed by P2X7 blockade with antagonist Brilliant Blue G (BBG). Then, we further noticed that GSK-1016790A injection increased the P2X7 expression of CCD, which was decreased by TRPV4 blockade with antagonist RN-1734 and HC-067047. Furthermore, we also discovered that the expressions of IL-1β and IL-6 were upregulated by GSK-1016790A injection but reduced by RN-1734 and HC-067047. Our results provide evidence that P2X7 contributes to development of neuropathic pain mediated by TRPV4 in the CCD model, which may be the basis for treatment of neuropathic pain relief.

To evaluate the clinical effects of 5-fluorouracil in different mass concentrations combined with triamcinolone in the treatment of keloids. From March 2018 to March 2019, 29 patients with 31 keloids receipted in the Department of Plastic Surgery of Fujian Medical University Union Hospital, 11 patients with 20 keloids receipted in the Department of Dermatology of Pingtan Comprehensive Experimental Area Hospital, and 9 patients with 9 keloids receipted in the Fuzhou Heisey-Dea Aesthetic Clinic were included in this prospectively randomized control study, with 27 males and 22 females, aged (30±9) years. According to the random number table, the keloids were divided into low mass concentration group (19 keloids, 17 patients), medium mass concentration group (21 keloids, 19 patients), and high mass concentration group (20 keloids, 17 patients). Then 5-fluorouracil at mass concentrations of 0.5, 5.0, and 12.5 mg/mL combined with triamcinolone acetonide were injected respectively, once every 4 weeks, for a total of 3 times. Before the first treatment and in 3 months after the last treatment, the appearance of keloids was evaluated by Vancouver Scar Scale (VSS) and pain and pruritus of keloids were evaluated by Visual Analogue Scale (VAS). Then the score differences before and after the treatment were calculated. In 6 months after the last treatment, the patients' efficacy satisfaction was evaluated by efficacy satisfaction rating scale. Adverse reactions during the treatment were recorded. In the follow-up of one year after the last treatment, the recurrence rates of keloids were counted. Data were statistically analyzed with chi-square test, one-way analysis of variance, paired sample test, least significant difference test, Wilcoxon rank sum test, Kruskal-Wallis rank sum test, or Fisher's exact probability test. Before the first treatment, the appearance VSS scores of appearance of keloids in the three groups were similar (0.039, >0.05). In 3 months after the last treatment, the appearance VSS scores of keloids in low mass concentration group were significantly higher than those in medium mass concentration group and high mass concentration group (=2.267, 4.086, <0.05 or <0.01). In 3 months after the last treatment, the appearance VSS scores of keloids in low mass concentration group, medium mass concentration group, and high mass concentration group were significantly decreased compared with those before the first treatment (=18.222, 44.272, 22.523, <0.01). The differences of appearance VSS scores of keloids in low mass concentration group before and after treatment were significantly lower than those in medium mass concentration group and high mass concentration group (=-4.096, -6.357, <0.01), and the differences of appearance VSS scores of keloids in medium mass concentration group before and after treatment were significantly lower than those in high mass concentration group (=-2.368, <0.05). Before the first treatment, the pain and pruritus VAS scores of keloids in the three groups were similar (=0.149, >0.05). In 3 months after the last treatment, the pain and pruritus VAS scores of keloids in low mass concentration group were significantly higher than those in medium mass concentration group and high mass concentration group (=2.191, 4.386, <0.05 or <0.01), and the pain and pruritus VAS scores of keloids in medium mass concentration group were significantly higher than those in high mass concentration group (=2.276, <0.05). In 3 months after the last treatment, the pain and pruritus VAS scores of keloids in medium mass concentration group and high mass concentration group were significantly decreased compared with those before the first treatment (-3.904, -3.844, <0.01). The differences of pain and pruritus VAS scores of keloids in low mass concentration group before and after treatment were significantly lower than those in medium mass concentration group and high mass concentration group (-4.265, -6.104, <0.01). In 6 months after the last treatment, the efficacy satisfaction scores of the corresponding patients of keloids were (88±8) points in high mass concentration group, which were significantly higher than (76±8) points in medium mass concentration group and (60±8) points in low mass concentration group (=-3.820, -6.675, <0.01), and the efficacy satisfaction scores of the corresponding patients of keloids in medium mass concentration group were significantly higher than those in high mass concentration group (=-2.984, <0.05). There was only statistically significant difference in pain within the 3 groups (<0.01). In the follow-up of one year after the last treatment, the recurrence rate of keloids in high mass concentration group was significantly lower than that in low mass concentration group (=8.313, <0.01), and the recurrence rate of keloids in medium mass concentration group was similar to the recurrence rates in low mass concentration group and high mass concentration group (>0.05). After treating keloids with high mass concentration of 5-fluorouracil combined with triamcinolone acetonide, the symptoms were significantly improved, the efficacy satisfaction of patients was increased, with no obvious adverse reactions but long lasting efficacy. Their overall effects are better than treatment using medium and low mass concentrations of 5-fluorouracil, which is worthy of clinical promotion.

To identify the etiologies of isolated fourth cranial nerve palsy in Ramathibodi hospital, Thailand.

Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis.

Crotamine is a polypeptide toxin isolated from rattlesnake venom. Although several studies have been developed identifying many biological effects of isolated crotamine, none of them evaluated its acute toxicity, antinociceptive, and anti-inflammatory activities through oral administration. All in vivo experiments from this study were performed in mice. The up-and-down procedure and hippocratic screening were carried out to evaluate possible pharmacological and toxic effects. Antinociceptive and anti-inflammatory activities of this toxin were evaluated using acetic acid-induced abdominal writhing, formalin-induced pain assays, croton oil-induced ear edema, and carrageenan-induced pleurisy. Crotamine did not cause lethality or signs of intoxication up to the maximum dose tested (10.88 mg/kg). The number of contortions was reduced significantly by 34, 57, and 74% at the oral doses of 0.08, 0.16, and 0.32 mg/kg, respectively. At the dose of 0.16 mg/kg, crotamine decreases pain time-reactivity at neurogenic phase by 45% and at inflammatory phase by 60%. Also, crotamine elicited antiedematogenic activity through the attenuation of the croton oil-induced ear edema by 77%. In the carrageenan-induced pleurisy, the leukocyte, neutrophil, and mononuclear cell migration to the lesion site were reduced by 52%, 46%, and 59%, respectively. Altogether, crotamine demonstrated in vivo antinociceptive and anti-inflammatory effect through acute oral administration, generating an anti-migratory mechanism of action at non-toxic doses.

Thoracic surgery is still associated with severe postoperative pain. In this video tutorial, we present 2 techniques that could be used as an additional method in a multimodal postoperative analgesia strategy for video-assisted thoracic surgery. We present the combination of an epipleural surgical infiltration of a local anesthetic with an ultrasound-guided erector spinae plane block.

Cerebral ischemia-reperfusion injury (CIRI) mainly arises from the clinical treatment of ischemic stroke, induced by the blood-brain barrier (BBB) disruption and infiltrated inflammation. The Sigma-1 receptor (Sigma-1R) is a novel target for neuroprotection, and the α2-receptor agonist pain medication dexmedetomidine displays a neuroprotective effect through activating Sigma-1R. The present study aims to investigate the potential therapeutic effect of dexmedetomidine in a mouse stroke model and hypoxia/reoxygenation(OGD/R)-induced brain endothelial dysfunction. First, we found that Sigma-1R was significantly upregulated in middle cerebral artery occlusion (MCAO) mice by the administration of dexmedetomidine. experiments revealed that dexmedetomidine ameliorated hyperpermeability of the blood-brain barrier (BBB), lowered the expression level of Occludin, and impaired brain function as measured by neurological scores in MCAO mice. assays show that dexmedetomidine alleviated OGD/R-caused cytotoxicity, hyperpermeability, abnormal expression of Occludin, and inflammatory factors in human brain microvascular endothelial cells (HBMVECs). Moreover, blockage of Sigma-1R by its antagonist BD1047 abolished the neuroprotective property of dexmedetomidine in both animal and cell culture experiments. On the basis of these findings, we conclude that dexmedetomidine therapy shows neuroprotection in MCAO mice. Mechanistically, dexmedetomidine alleviated hypoxia/reoxygenation-induced cerebral endothelial dysfunction by activating the Sigma-1R-mediated signaling pathway.

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes, but the molecular mechanisms of DPN are still unclear.

As alternatives, metallic/nonmetallic bone graft materials play significant roles in bone defect surgery to treat external trauma or bone disease. However, to date, there are rather limited long-term implantable materials owning to in situ molding incapability of metallics and poor mechanical property of nonmetallics. Here, Bi-based low melting point alloy, with unique properties of injectability, solid-liquid phase transition, mechanical capability, and biocompatibility, present obvious long-lasting bone affinity as the excellent artificial bone-substitute. It is particularly necessary to point out that the targeted injected Bi alloy remains in its original position for up to 210 days without moving, as well as, displays good osseointegration ability to resolve repeated revision trauma caused by losing bone repair material. Additionally, with outstanding electrical and thermal conductivity, an unconventional way using Bi alloy to realize very beneficial hyperthermia analgesia via non-invasive wireless energy delivery is first proposed, which avoids adverse effects on bone remodeling inflicted by traditional drugs. The significantly decreased expression of pain sensitizing factor, such as, interleukin-6, neuropeptide substance, and transient receptor potential vanilloid 1 reveals the potential mechanism of hyperthermia analgesia. The present findings suggest the combination therapy of Bi alloy in bone repair and analgesia, which owns far-reaching clinical application value.

Small intestinal neuroendocrine neoplasms (siNENs) are slowly growing tumours with a low malignant potential. However, more than half of the patients present with distant metastases (stage IV) and nearly all with locoregional lymph node (LN) metastases at the time of surgery. The value of locoregional treatment is discussed controversially.